ABSTRACT
Production of IL-2 and IFN-gamma by CD4+ T lymphocytes is important for the maintenance of a functional immune system in infected individuals. In the present study, we assessed the cytokine production profiles of functionally distinct subsets of CD4+ T lymphocytes in rhesus monkeys infected with pathogenic or attenuated SIV/simian human immunodeficiency virus (SHIV) isolates, and these responses were compared with those in vaccinated monkeys that were protected from immunodeficiency following pathogenic SHIV challenge. We observed that preserved central memory CD4+ T lymphocyte production of SIV/SHIV-induced IL-2 was associated with disease protection following primate lentivirus infection. Persisting clinical protection in vaccinated and challenged monkeys is thus correlated with a preserved capacity of the peripheral blood central memory CD4+ T cells to express this important immunomodulatory cytokine.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV/immunology , Interleukin-2/biosynthesis , Simian Immunodeficiency Virus/immunology , AIDS Vaccines/pharmacology , Animals , CD28 Antigens/metabolism , Gene Products, gag , HIV/pathogenicity , HIV Infections/immunology , HIV Infections/prevention & control , HIV Infections/virology , Humans , Immunologic Memory , In Vitro Techniques , Interferon-gamma/biosynthesis , Macaca mulatta , RNA, Viral/blood , SAIDS Vaccines/pharmacology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/pathogenicity , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor-alpha/biosynthesis , fas Receptor/metabolismABSTRACT
The magnitude and durability of immune responses induced by replication-defective adenovirus serotype 5 (ADV5) vector-based vaccines were evaluated in the simian-human immunodeficiency virus/rhesus monkey model. A single inoculation of recombinant ADV5 vector constructs induced cellular and humoral immunity, but the rapid generation of neutralizing anti-Ad5 antibodies limited the immunity induced by repeated vector administration. The magnitude and durability of the immune responses elicited by these vaccines were greater when they were delivered as boosting immunogens in plasmid DNA-primed monkeys than when they were used as single-modality immunogens. Therefore, administration of ADV5-based vectors in DNA-primed subjects may be a preferred use of this vaccine modality for generating long-term immune protection.
Subject(s)
Adenoviruses, Human/immunology , Antibodies, Viral/blood , Genetic Vectors/immunology , HIV Infections/immunology , Immunization, Secondary , Simian Acquired Immunodeficiency Syndrome/immunology , T-Lymphocytes/immunology , Vaccination , Viral Vaccines/immunology , AIDS Vaccines/administration & dosage , AIDS Vaccines/immunology , Adenovirus E1 Proteins/genetics , Adenovirus E3 Proteins/genetics , Adenoviruses, Human/genetics , Animals , Drug Evaluation, Preclinical , Gene Deletion , Genetic Vectors/genetics , HIV Antibodies/blood , HIV-1/genetics , HIV-1/immunology , Injections, Intramuscular , Macaca mulatta , Neutralization Tests , Plasmids/genetics , Simian Acquired Immunodeficiency Syndrome/blood , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology , Viral Vaccines/administration & dosageABSTRACT
Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.
